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Glucocorticosteroids are the most effective anti-inflammatory drugs for the treatment of asthma. The primary mechanisms of action of these agents include interference with arachidonic acid metabolism, prevention of directed migration and activation of inflammatory cells and increased responsiveness of ß-receptors in airway smooth muscle.1 With the advent of highly potent inhaled glucocorticosteroids and other asthma therapies, long-term treatment with oral glucocorticosteroids is now seldom required to control asthma. Given the side-effects associated with both short- and long-term use of these agents, doses should be kept to the minimum necessary to achieve the desired level of asthma control.
The response to oral glucocorticosteroids may be quite variable. Patients with glucocorticosteroid-resistant asthma2 have a baseline FEV1 of less than 60% of the predicted value, a bronchodilator response of the FEV1 greater than 30% of baseline and a change in FEV1 in response to a 7-day course of oral glucocorticosteroids (20 mg of prednisone per day) of less than 15%. In contrast, responsive patients show an improvement in FEV1 of greater that 30% at any time during the 7-day course of systemic glucocorticosteroid. In resistant patients, diurnal variability in PEF and a brisk bronchodilator response are common.3 Resistant patients typically show little improvement in FEV1 or PEF despite administration of high doses of systemic glucocorticosteroids for up to 2 weeks.4,5
No universally accepted definition of glucocorticosteroid-resistant asthma yet exists,4 although Leung and Szefler6 proposed that it be defined as failure to improve baseline morning prebronchodilator FEV1 by >15% of the predicted value after at least 7-14 days of 40 mg oral prednisone or its equivalent (20 mg twice daily). The term "glucocorticosteroid-resistant asthma" is misleading as applied to most patients, because their glucocorticosteroid resistance is not absolute, but rather a shift of the dose-response curve to the right.
The third group, glucocorticosteroid-dependent patients, typically have severe asthma, require high doses of inhaled glucocorticosteroids and regular oral glucocorticosteroids (usually < 40 mg/day) to manage their symptoms.1 Control of their asthma often deteriorates when their dose of oral glucocorticosteroid is reduced.1
Carmichael and colleagues7 suggest that such features as longer duration of symptoms, morning fall in FEV1, greater bronchial reactivity to methacholine and a positive family history may, to some extent, distinguish nonresponders from responders. Other mechanisms of glucocorticosteroid-resistant asthma have also been proposed.8
Patients should not be labeled as resistant to glucocorticosteroid until factors related to asthma care have been examined (Table 1). If conventional therapeutic options fail to achieve reasonable control, or if control is achieved only with high doses of systemic glucocorticosteroids, alternative therapies using nonsteroidal immunosuppressive agents may be considered in some patients.
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Methotrexate
In low doses, methotrexate appears to inhibit the attraction of polymorphonuclear cells by leukotriene B4 and interleukin-1.9 A review by the working group for the Canadian Asthma Consensus Conference8 on the role of methotrexate in chronic severe asthma described results of many randomized, placebo-controlled clinical trials. These suggested that use of methotrexate has a significant glucocorticosteroid-sparing effect, although some studies did not show additional improvements in pulmonary function.8 More recently, a placebo-controlled, randomized, double-blind, parallel-group study10 reported only marginal reduction in glucocorticosteroid use in 16 weeks of methotrexate treatment in 24 patients with severe asthma. Another 24-week, placebo-controlled, double-blind parallel-group study, which included a crossover arm at 12 weeks,11 found that methotrexate (15 mg/week) resulted in a 38% reduction in oral glucocorticosteroid use and a 22% decrease in daily bronchodilator use but no improvement in lung function in 12 patients with severe asthma.
A recent meta-analysis12 set out to determine whether treatment with low-dose methotrexate spares oral glucocorticosteroids in adults. It excluded studies that did not contain original data related to the primary question, had no controls or described patients younger than 18 years of age. The remaining 11 eligible studies all included an initial phase in which the baseline level of prednisone was reduced to the lowest possible dose. Methotrexate treatment resulted in a decrease in prednisone or prednisolone usage by an average of 4.37 mg/d or 23.7% of the initial dosage. The greatest effect was evident in patients whose glucocorticosteroid dose was reduced during the initial phase and in those who received treatment with methotrexate for 24 weeks.
Methotrexate in low doses (usually 5-25 mg weekly administered on a single day) has been used for the treatment of severe asthma for almost a decade with usually infrequent and minor side-effects. Increasing doses may be accompanied by an increase in side-effects, especially anorexia, diarrhea or nausea and vomiting. Other side-effects include leukopenia, which is unpredictable and can be life-threatening; hepatic fibrosis (risks factor being cirrhosis, alcoholism, obesity and diabetes); pulmonary toxicity (acute pneumonitis and insidious interstitial fibrosis); and opportunistic infections such as Pneumocystis carinii pneumonia, pulmonary cryptococcosis and nocardiosis.13
It is unclear why various investigators have obtained different results, but this may be related to the heterogeneity of study populations and the lack of consensus on what is meant by glucocorticosteroid-resistant and dependent asthma. At present, it is difficult to predict which patients will respond to methotrexate and further studies are required to define who is most likely to benefit. Methotrexate should be considered only in patients with severe asthma in whom optimal conventional therapy has failed to achieve adequate control and when there is concern about the side-effects of glucocorticosteroids.
Cyclosporine A
Cyclosporine is a potent nonselective anti-inflammatory agent that acts primarily by inhibiting transcription factors for cytokines derived from T lymphocytes.14-16 Few well-controlled trials have examined the efficacy of cyclosporine in the treatment of chronic severe asthma. In an uncontrolled study,17 6 of 12 patients on cyclosporine (3 mg/kg daily) reduced their daily glucocorticosteroid dose and experienced an improvement in symptoms and PEF. In a 24-week double-blind, randomized, crossover trial in 30 patients18 cyclosporine use (initial dose of 5 mg/kg daily, aiming at trough concentrations of 100-250 µg/L) was associated with a 12% increase in PEF and a 17.6% increase in FEV1. This study was not designed to examine the glucocorticosteroid-sparing effect of cyclosporine.
In a double-blind, placebo-controlled, randomized, parallel-group study involving 34 glucocorticosteroid-dependent patients with asthma (mean oral prednisone dose, 16 mg/d),15 cyclosporine use over 34 weeks was associated with a slight beneficial effect on some subjective indicators of asthma severity, but no improvements in pulmonary function and no difference in the final dose reduction of prednisone between the treatment groups. The authors suggested a limited place for cyclosporine use in the treatment of patients with asthma who are dependent on glucocorticosteroids.
More recently, a double-blind placebo-controlled study19 in 39 patients who were dependent on glucocorticosteroid found that cyclosporine A (initial dose, 5 mg/kg daily) was associated with a 62% reduction in prednisolone use (from 10 to 3.5 mg) but only a 25% reduction (from 10 to 7.5 mg) with placebo (p < 0.05). The reduction in glucocorticosteroid dose was most pronounced during the last 12 weeks of the 36-week active treatment period. Patients receiving cyclosporine also exhibited a significant (9.4%) improvement in PEF.
Cyclosporine should be given in 2 doses, usually starting at 3 mg/kg a day (based on ideal body weight) and aiming at trough concentrations close to 150 mg/L; its administration requires close monitoring of blood pressure, renal function, white blood cell count and level of cyclosporine in the blood. Side-effects include hypertension, renal failure, hypertrichosis and paresthesia.
There is conflicting evidence concerning the value of cyclosporine in patients with asthma who are dependent on or resistant to glucocorticosteroid treatment. It is not known if there is a sustained clinical benefit after stopping cyclosporine treatment; indeed, this drug has many potential side-effects that may be more serious than those associated with prednisone.
Gold salts
Gold has been used to treat refractory rheumatoid arthritis for many years. It inhibits immunoglobulin E-mediated release of histamine and leukotriene C4 from basophils and mast cells.20 In the first double-blind, placebo-controlled study showing that gold was of some benefit in asthma,21 79 patients with asthma of variable severity, some of whom required glucocorticosteroids, were treated with gold salts or placebo for 30 weeks: 71% of those in the treated group improved compared with only 44% of the control group. A 22-week, double-blind study22 compared intramuscular gold therapy with placebo in 9 asthmatic patients requiring high doses of prednisone. While on gold therapy, 5 of the patients reduced their need for glucocorticosteroid; 2 had to stop gold therapy because of severe proteinemia.
There is more convincing evidence that oral gold, auranofin, reduces the need for glucocorticosteroids in dependent asthmatic patients. In an open trial of severe glucocorticosteroid-dependent asthmatic patients, auranofin allowed reduction in oral glucocorticosteroids with improvement in methacholine-invoked bronchial responsiveness without deterioration of spirometric measures of lung function.23 A double-blind, controlled study comparing auranofin (3 mg twice daily) with placebo24 followed 28 asthmatic adult patients requiring at least 2.5 mg of prednisone daily (mean 7.6 ± 5.3 mg) for 26 weeks. Auranofin significantly reduced glucocorticosteroid use by 4 mg/d (versus 0.3 mg/d in the placebo group), asthma symptoms and exacerbations and improved FEV1.
In a recent, large 6-month double-blind placebo-controlled multicentre study,25 all patients were severely asthmatic, were taking low-dose inhaled glucocorticosteroids and required at least 10 mg of prednisone daily for at least 3 months. On the 157 people who completed the study, 82 were taking 3 mg auranofin twice daily. The primary efficacy end-point (i.e., a reduction of at least 50% of the oral glucocorticosteroid dose from baseline) was achieved in a significantly higher proportion of the auranofin group (41%) than the placebo group (27%). The glucocorticosteroid-sparing effect of auranofin was most pronounced in those requiring 10-19 mg of prednisone daily at baseline.
Oral gold is preferred to the parenteral formulation. Side-effects are frequent and include urticaria, stomatitis, leukopenia, thrombocytopenia and proteinuria. Therefore, close monitoring via complete blood counts and urine analyses is required. Although it can be concluded that 3 mg auranofin twice daily reduces the need for oral glucocorticosteroids in asthma, its exact role and risk-benefit ratio compared with oral glucocorticosteroids is still not well defined.
Intravenous immunoglobulin
Intravenous immunoglobulin is currently being evaluated for possible therapeutic benefit in many diseases including asthma. No double-blind controlled study is yet available, and 2 uncontrolled studies26,27 in children showed conflicting results. In a recent open study,28 intravenous immunoglobulin allowed a marked reduction in the dose of oral glucocorticosteroids in 2 glucocorticosteroid-insensitive asthmatic adults accompanied by improvements in FEV1 and a decrease in the variability of PEF. With so little scientific evidence, it is impossible to recommend the use of intravenous immunoglobulin in the treatment of glucocorticosteroid-resistant asthma.
Other agents in severe asthma
Dapsone29 and hydroxychloroquine30 have been tested in small uncontrolled studies that may suggest a potential role in the treatment of severe glucocorticosteroid-dependent patients with asthma. However, in a 2-month double-blind crossover study,31 hydroxychloroquine was of no benefit in glucocorticosteroid-dependent asthma. There is little evidence to support the use of these drugs in severe asthma.
Unconventional therapies
Conventional medical management of asthma relies on control of the environment, a number of drugs and, occasionally, special techniques such as immunotherapy. Each approach is based on reasonable and sound science and many are associated with long-lasting success. However, the annals of asthma therapy are replete with alternative, unproven and mystic therapies, and reliance on drugs that are often progenitors of many of those still in favour today. These have always been popular and often have a long history of use. Recently, interest in their use has been growing. After interviewing 1539 adults, Eisenberg and colleagues32 concluded that a third of adults in the United States use alternative, unconventional therapies, and 25% of those treated conventionally also use unconventional remedies. Information about the use of alternative therapies by asthmatic adults is unavailable, but some figures are available for Canadian asthmatic children. Spigelblatt and co-workers33 found that 208 (11%) of 1911 children had previously consulted one or more unconventional practitioners. Chiropractic, homeopathy, naturopathy and acupuncture together accounted for 84% of use.
Only a limited number of well-controlled studies have addressed the value of unconventional therapies, the most popular of which are homeopathy, acupuncture, osteopathy, chiropractic, herbal medicines, hypnosis, yoga and Chinese, Japanese and Indian therapies. Ziment34,35 has recently reviewed these therapies comprehensively. There is no objective evidence for any real benefit of these approaches.
Nevertheless, some patients will try these approaches and may even benefit. Most authors agree that they may indeed lead to an improvement in asthma control, but this is no different from a placebo effect; however, a placebo is more effective than no therapy in asthma.35 Placebo responses occur in about a third of patients, but a much higher response is not infrequent and explains the positive results in some uncontrolled double-blind studies.
Physicians must show empathy toward patients who seek help from unconventional sources; however, they should explain the lack of scientific evidence and urge their patients not to stop their anti-asthma drugs, particularly anti-inflammatory drugs, in an uncontrolled way.
Homeopathy
In the only double-blind, parallel-group, placebo-controlled study36 of the effect of homeopathy in asthma, 11 of 24 atopic asthmatic adults received homeopathic treatment for 4-8 weeks. More than two-thirds of the participants were taking inhaled glucocorticosteroids at baseline and did not modify their treatment. Although there was a significant improvement in the visual analog scale for symptoms in the treated group after the first week, there was no significant improvement in FEV1 or histamine-provoked bronchial responsiveness. However, the effect seems very small, and a larger well-controlled study is needed to clarify homeopathy's role in the treatment of asthma.
Chiropractic
Although widely used in the treatment of asthma, specific chiropractic spinal manipulation was not effective in asthmatic adults in a recent double-blind, controlled study.37
Acupuncture
No good controlled study of the role of acupuncture in the treatment of asthma has shown an adequate response.38 Fung and colleagues39 found some mild protection against exercise-induced asthma in a placebo-controlled single-blind study.39 In contrast, 2 well-controlled double-blind, crossover studies40,41 failed to show any short- or long-term benefit of acupuncture over placebo in adults with asthma. Complications associated with acupuncture include transmission of disease (e.g., hepatitis B and C, HIV infection) and pneumothorax and local infections.
Hypnosis and relaxation techniques
It has long been recognized that relaxation techniques, including yoga, may improve the well-being of patients, and some open or single-blind studies have suggested a possible role for hypnosis, relaxation techniques or yoga in the treatment of asthma or in reducing bronchial hyper-responsiveness.42 No well-controlled, double-blind randomized study has looked adequately at the role of such therapy.
Herbal medicine and Chinese, Japanese and Indian medicines
Although these approaches are popular in some countries, they have not been subjected to the scrutiny of a well-controlled, double-blind randomized study.
Suggestions for future research
• Research is needed to determine why some patients with asthma do not respond favourably to glucocorticosteroid therapy.
• Research is required to improve understanding of the interaction between airway remodeling, hyperresponsiveness and inflammation.
• Large, well-controlled trials are needed to evaluate the potential benefits of methotrexate in severe asthma. Further studies on the pharmacokinetics of low-dose methotrexate using different routes of administration may explain why some patients respond more positively than others.
• Given the significant side-effects associated with orally administered cyclosporine, the development of an inhaled formulation may prove beneficial; more studies are needed to determine the exact role of this drug.
• The place of auranofin in the treatment of glucocorticosteroid-dependent patients with asthma must be better defined, although there is good evidence that it has some glucocorticosteroid-sparing effects.
• Well-designed placebo-controlled studies are urgently needed to determine the role of unconventional therapies in the treatment of asthma, particularly homeopathy and acupuncture.
Recommendations
• In chronic severe asthma that seems unresponsive to moderate doses of oral glucocorticosteroids, confounding issues should be assessed before increasing the dose of oral glucocorticosteroids or using other immunosuppressive agents (level I).
• Because of the associated clinical problems, patients with asthma who have a severe glucocorticosteroid dependence requiring further intervention should be referred to a specialized centre (level III).
• Potentially toxic immunosuppressive agents, such as methotrexate, cyclosporine and gold salts, should be reserved for patients with severe asthma who are dependent on long-term high-dose oral glucocorticosteroids and should be used only in specialized centres (level III).
• There is no objective evidence of any benefit, apart from placebo effect, from the more frequently used unconventional therapies such as acupuncture, chiropractic, homeopathy, naturopathy, osteopathy and herbal remedies (level I or III, depending on the therapy).
References
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Copyright 1995-1999, Canadian Medical Association. All rights reserved. ISSN 1488-2329
(e) 0820-3946 (p)
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association. |
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